Methods of preparing polymorphic form A of bazedoxifene acetate

ABSTRACT

The present invention relates to methods of preparing polymorphic Form A of bazedoxifene acetate and polymorphic Form A prepared by such methods.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority under 35 U.S.C. §119(e)to U.S. Patent Application Ser. No. 61/027,634 filed Feb. 11, 2008,which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to methods of preparing polymorphicForm A of bazedoxifene acetate; and polymorphic Form A of bazedoxifeneacetate prepared by such methods.

BACKGROUND OF THE INVENTION

Bazedoxifene acetate has a chemical name of(1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-olacetic acid) and has the chemical structure shown below:

Bazedoxifene acetate belongs to the class of drugs typically referred toas selective estrogen receptor modulators (SERMs). Consistent with itsclassification, bazedoxifene demonstrates affinity for estrogenreceptors (ER) but shows tissue selective estrogenic effects. Forexample, bazedoxifene acetate demonstrates little or no stimulation ofuterine response in preclinical models of uterine stimulation.Conversely, bazedoxifene acetate demonstrates an estrogen agonist-likeeffect in preventing bone loss and reducing cholesterol in anovariectomized rat model of osteopenia. In an MCF-7 cell line (humanbreast cancer cell line), bazedoxifene acetate behaves as an estrogenantagonist. These data demonstrate that bazedoxifene acetate isestrogenic on bone and cardiovascular lipid parameters andantiestrogenic on uterine and mammary tissue and thus has the potentialfor treating a number of different disease or disease-like states inwhich the estrogen receptor is involved.

U.S. Pat. Nos. 5,998,402 and 6,479,535 report the preparation ofbazedoxifene acetate and characterize the salt as having a melting pointof 174°-178° C. The synthetic preparation of bazedoxifene acetate hasalso appeared in the general literature. See, for example, Miller etal., J. Med. Chem., 2001, 44, 1654-1657, which reports the salt as acrystalline solid having a melting point of 170.5-172.5° C. Furtherdescription of the drug's biological activity has also appeared in thegeneral literature (e.g., Miller, et al., Drugs of the Future, 2002,27(2), 117-121).

It is well known that the crystalline polymorph form of a particulardrug is often an important determinant of the drug's ease ofpreparation, stability, solubility, storage stability, ease offormulation and in vivo pharmacology. Polymorphic forms occur where thesame composition of matter crystallizes in a different latticearrangement resulting in different thermodynamic properties andstabilities specific to the particular polymorphic form. In cases wheretwo or more polymorph substances can be produced, it is desirable tohave a method to make both polymorphs in pure form. In deciding whichpolymorph is preferable, the numerous properties of the polymorphs mustbe compared and the preferred polymorph chosen based on the manyphysical property variables. It is entirely possible that onepolymorphic form can be preferable in some circumstances where certainaspects such as ease of preparation, stability, etc. are deemed to becritical. In other situations, a different polymorph may be preferredfor greater solubility and/or superior pharmacokinetics.

Polymorphic Form A of bazedoxifene acetate is disclosed in US2005/0227965 while polymorphic Form B of bazedoxifene acetate isdisclosed in US 2005/0250762. Form A has higher solubility in bothaqueous and organic solvent systems than Form B. This is particularlyadvantageous in formulations or doses where the solubility of theparticular composition is of concern. For example, higher solubility caninfluence bioavailability, which can affect biological absorption anddistribution of the drug, as well as can facilitate formulation inliquid carriers. However, Form A is the kinetic (or meta-stable)polymorph, while Form B is the thermodynamically more stable polymorph.Form A can easily convert to Form B upon contact with a solvent orsolvent mixture (e.g., ethyl acetate and ethanol), which presents achallenge to the preparation of pure Form A that is substantially freeof Form B.

Because polymorphic Form A of bazedoxifene acetate provides betterbioavailability in some drug formulations, there is a need for a new andpractical method that can reliably produce pure polymorphic Form A ofbazedoxifene acetate. The methods of preparing polymorphic Form A ofbazedoxifene acetate described herein help meet these and other needs. Amethod of preparing polymorphic Form A of bazedoxifene acetate is alsodisclosed in a commonly assigned and co-pending U.S. Patent ApplicationSer. No. 61/027,607, filed on Feb. 11, 2008.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In addition, the materials, methods, andexamples are illustrative only and not intended to be limiting.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to a method of preparingpolymorphic Form A of bazedoxifene acetate, the method comprising:

(a) contacting hexamethylenimino benzyloxyindole with hydrogen in asolvent comprising ethanol, and in the presence of a catalyst atelevated temperature to provide a first reaction mixture comprisingbazedoxifene free base, wherein the first reaction mixture issubstantially free from hexamethylenimino benzyloxyindole;

(b) treating said first reaction mixture with an antioxidant to providea second reaction mixture;

(c) filtering said second reaction mixture to provide a solutioncomprising bazedoxifene free base; and

(d) treating said solution with acetic acid to crystallize polymorphicForm A of bazedoxifene acetate.

In another aspect, the present invention relates to a method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate,the method comprising keeping said polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with asolvent.

In yet another aspect, the present invention relates to a method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate,the method comprising keeping said polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with thevapor of a solvent.

In a further aspect, the present invention relates to a polymorphic FormA of bazedoxifene acetate prepared according to the methods describedherein.

Other features and advantages of the invention will be apparent from thedetailed description, drawings, and from the claims.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 shows an overlay of IR spectra of polymorphic Form A and Form Bof bazedoxifene acetate (the bottom portion of FIG. 1 corresponds toForm A and the top portion corresponds to Form B).

FIG. 2 shows a DSC thermogram for polymorphic Form A of bazedoxifeneacetate.

FIG. 3 shows a DSC thermogram for polymorphic Form B of bazedoxifeneacetate.

FIG. 4 shows an overlay of DSC thermograms for polymorphic Form A andForm B of bazedoxifene acetate.

FIG. 5 is a DSC thermogram for polymorphic Form A of bazedoxifeneacetate showing an example of a Form A batch with a content of Form Bless than 0.1% w/w.

FIG. 6 shows a TGA curve for polymorphic Form A of bazedoxifene acetate.

FIG. 7 shows a TGA curve for polymorphic Form B of bazedoxifene acetate.

FIG. 8 shows the content of polymorphic Form B vs. time and vs.temperature for a sample of polymorphic Form A bazedoxifene acetate thatis wet of EtOH.

FIG. 9 shows the content of polymorphic Form B vs. time and vs.temperature for a sample of polymorphic Form A bazedoxifene acetate thatis wet of EtOAc.

DETAILED DESCRIPTION OF THE INVENTION

Polymorphic Form A of bazedoxifene acetate has higher solubility in bothaqueous and organic solvent systems than polymorphic Form B ofbazedoxifene acetate. As a result, Form A of bazedoxifene acetateprovides better bioavailability in drug formulations. However, Form A isthe kinetic (or meta-stable) polymorph while Form B is thethermodynamically more stable polymorph. Form A can easily convert toForm B upon contact with a solvent or solvent mixture (e.g., ethylacetate and ethanol), which presents a challenge to the preparation ofpure Form A that is substantially free of Form B. The present inventionmeets this challenge by providing methods of preparing pure Form A thatis substantially free of Form B.

In one aspect, the present invention provides a method of preparingpolymorphic Form A of bazedoxifene acetate, the method comprising:

(a) contacting hexamethylenimino benzyloxyindole with hydrogen in asolvent comprising ethanol, and in the presence of a catalyst atelevated temperature to provide a first reaction mixture comprisingbazedoxifene free base, wherein the first reaction mixture issubstantially free from hexamethylenimino benzyloxyindole;

(b) treating said first reaction mixture with an antioxidant to providea second reaction mixture;

(c) filtering said second reaction mixture to provide a solutioncomprising bazedoxifene free base (i.e., bazedoxifene that is free ofacid, e.g., acetic acid); and

(d) treating said solution with acetic acid to crystallize polymorphicForm A of bazedoxifene acetate.

The term “substantially free” as used herein refers to a compound or amixture that contains less than 10% of an undesired compound orimpurity, preferably less than 5% of an undesired compound or impurity,and more preferably less than 1% of an undesired compound or impurity,e.g., less than 0.5% or less than 0.1% of an undesired compound orimpurity. For example, “Compound A is substantially free of Compound B,or Mixture C is substantially free of Compound B” means that Compound Aor Mixture C contains less than 10% of Compound B, preferably less than5% of Compound B, and more preferably less than 1% of Compound B. e.g.,less than 0.5% of Compound B or less than 0.1% of Compound B.

In certain embodiments, in step (a) of the method described herein, thesolvent further comprises at least one solvent selected from the groupconsisting of ethyl acetate, acetone, cyclohexane and methanol, forexample, ethanol-ethyl acetate, ethanol-acetone-cyclohexane,ethanol-methanol-cyclohexane, and so forth. In one embodiment, thesolvent comprises ethanol and ethyl acetate.

In certain embodiments, step (a) of the method described herein iscompleted in less than about 10 hours. In certain other embodiments,step (a) is completed in less than about 6 hours. In furtherembodiments, step (a) is completed in less than about 4 hours, forexample, in less than about 3 hours or about 2 hours.

In certain embodiments, in step (a) of the method described herein, thecatalyst is a Pd/C catalyst. In one embodiment, the Pd/C catalyst usedis in an amount less than about 10 mmol per mol of hexamethyleniminobenzyloxyindole used. In another embodiment, the Pd/C catalyst used isin an amount less than about 6 mmol per mol of hexamethyleniminobenzyloxyindole used.

In a further embodiment, the Pd/C catalyst has a total surface area(B.E.T) of more than about 1100 m²/g. In one embodiment, the Pd/Ccatalyst has a total surface area (B.E.T) of more than about 1500 m²/g.B.E.T. refers to Brunauer-Emmett-Teller and is a surface areameasurement technique applied to large surface area 1-20 m²/g materialsand based on adsorbed gas (e.g. N₂ at low temperature) as a function ofpressure (monolayer coverage). See, e.g., G. A. Somorjai, Principles ofSurface Chemistry, Prentice-Hall, Englewood Cliffs, N.J., 1972, p. 216.

In one embodiment, the Pd/C catalyst is non-reduced Pd on moist carbonand wherein the Pd/C catalyst is Engelhard 5% Pd on Carbon Powder DeLinkcode 5398. In another embodiment, the Pd/C catalyst is Engelhard 5% Pdon Carbon Powder catalyst code 5016. Both catalysts can be purchasedfrom Engelhard Corporation, Iselin, N.J.

The two catalysts present very different physical-chemicalcharacteristics. Table 1 below shows the principal characteristics ofthe two catalysts.

TABLE 1 CATALYST: 5% Pd on Carbon 5% Pd on Carbon Power Power DeLinkCODE 5016 5398 Total Surface Area 1100 1500 (B.E.T.) m²/g Particle Size10% < 5 microns 10% < 6 microns Distribution (Laser) 50% < 18 microns50% < 38 microns 90% < 96 microns 90% < 75 microns Active MetalPalladium Palladium Active Metal Content 5% on dry basis 5% on dry basisMetal Distribution Uniform Eggshell Type Reduced/Moist Unreduced/Moist

In certain embodiments, step (a) of the method described herein iscarried out at a temperature of about 30° C. or higher (up to about 78°C., e.g., about 75° C., about 70° C., about 65° C., about 60° C., about55° C., about 50° C., about 45° C., about 40° C., or about 35° C.). Incertain other embodiments, step (a) is carried out at a temperature ofabout 40° C. or higher (up to about 78° C., e.g., about 75° C., about70° C., about 65° C., about 60° C., about 55° C., about 50° C., or about45° C.). In yet other embodiments, step (a) is carried out at atemperature between about 30° C. to about 50° C. In yet otherembodiments, step (a) is carried out at a temperature between about 40°C. to about 50° C. In another embodiment, step (a) is carried out at atemperature of about 50° C.

In certain embodiments, in step (b) of the method described herein, saidantioxidant is selected from ascorbic acid, sodium ascorbate, ascorbylpalmitate, citric acid, propyl gallate, alpha Tocopherol (vitamin E),vitamin E TPGS, vitamin E acetate, butylated hydroxytoluene, butylatedhydroxyanisole and mixtures thereof. In another embodiment, saidantioxidant is ascorbic acid.

In certain embodiments, step (d) of the method described herein isfacilitated by seeding with polymorphic Form A of bazedoxifene acetate.In certain other embodiments, step (d) is carried out at a temperatureof about 40° C. or lower (as low as 0° C., e.g., 35° C.; 30° C., 25° C.,20° C., 15° C., 10° C., or 5° C.). In yet other embodiments, step (d) iscarried out at a temperature of about 30° C. or lower (as low as 0° C.,e.g., 25° C., 20° C., 15° C., 10° C., or 5° C.). In yet otherembodiments, step (d) is carried out at a temperature ranging from about0° C. to about 40° C. In yet other embodiments, step (d) is carried outat a temperature ranging from about 0° C. to about 30° C. In certainembodiments, step (d) is carried out at a temperature ranging from about20° C. to about 35° C. In certain other embodiments, step (d) is carriedout at a temperature ranging from about 25° C. to about 30° C. In yetother embodiments, step (d) is carried out at a temperature ranging fromabout 28° C. to about 30° C.

In certain embodiments, steps (a) through (d) of the method describedherein are conducted under inert atmosphere. Non-limiting examples ofinert atmosphere include nitrogen, argon, and so forth.

In certain embodiments, in step (d) of the method described herein, saidpolymorphic Form A of bazedoxifene acetate is more than 99% w/w pure,for example, more than 99.9% w/w pure. In certain other embodiments, instep (d) of the method described herein, said polymorphic Form A ofbazedoxifene acetate contains less than 1% w/w of Form B, for example,less than 0.1% w/w Form B.

In another aspect, the present invention provides a method of preparingpolymorphic Form A of bazedoxifene acetate, the method comprising:

(a) contacting hexamethylenimino benzyloxyindole with hydrogen in asolvent comprising ethanol, and in the presence of a catalyst atelevated temperature to provide a first reaction mixture comprisingbazedoxifene free base, wherein the first reaction mixture issubstantially free from hexamethylenimino benzyloxyindole;

(b) treating said first reaction mixture with an antioxidant to providea second reaction mixture;

(c) filtering said second reaction mixture to provide a solutioncomprising bazedoxifene free base;

(d) treating said solution with acetic acid to crystallize polymorphicForm A of bazedoxifene acetate; and

(e) isolating polymorphic Form A of bazedoxifene acetate by filtration,washing and drying.

In certain embodiments, in step (e) of the method described herein, saiddrying is conducted in an agitated filter dryer. An agitated filterdryer is useful in separating solids from liquid in a single vessel.Once the dryer is charged with slurry, pressure is either applied fromthe top of the filter dryer using a gas, such as nitrogen, or a vacuumis pulled from beneath the filter media, thereby forcing or pullingliquid through the cloth or mesh to generate a cake. Low pressures aregenerally used (e.g., 1 bar) to keep the cake from becoming socompressed that the crystals fuse together. The liquid exits at thebottom of the vessel. While the crystals are collecting on the filtermedia, the smooth edge of the agitator acts to smooth the surface of thecake so there are no crevices. The other edge of the agitator, which canrotate in both directions, might have teeth for digging into the cake tohelp break it up and remove it from the filter media. The cake might bebroken up and washed several times to remove all trace solvents orimpurities. Heat may be applied to dryer to speed up the drying process.

The stirring frequency, instantaneous duration, total stirring durationand drying duration of the dryer may vary depending on, inter alia, theload of the product to be dried. In one embodiment, the stirringfrequency is about 120 min., the instantaneous duration is about 2 min.,the total stirring duration is about 18 min. and the drying duration isabout 18 hours. In another embodiment, the stirring frequency is about30 min., the instantaneous duration is about 1 min., the total stirringduration is about 38 min. and the drying duration is about 19 hours. Inyet another embodiment, the stirring frequency is about 60 min., theinstantaneous duration is about 1 min., the total stirring duration isabout 18 min. and the drying duration is about 18 hours. In a furtherembodiment, the wet product is left at low temperature (e.g., about 0°C.) under nitrogen flow without stirring for a short period of time(e.g., about 1 hour) to reduce the product humidity level before thebeginning of the drying process.

In certain other embodiments, in step (e) of the method describedherein, said drying is conducted in a tumble dryer. The drying can beconducted in a tumble dryer under nitrogen, and/or vacuum conditions.The tumble dryer can be purchased from a variety vendors, for example,Italvacuum CRIOX in Italy.

In a further aspect, the present invention is directed to a method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate.The method includes keeping said polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with asolvent. In one embodiment, the solvent can totally or partiallydissolve said polymorphic Form A of bazedoxifene acetate.

In another aspect, the present invention is directed to a method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate.The method includes keeping the polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with asolvent and keeping the polymorphic Form A of bazedoxifene acetate at atemperature below 25° C. or lower (as low as about −196 C, e.g., about20° C., about 15° C., about 10° C., about 5° C., about 0° C., about −5°C., about −10° C., about −20° C., about −30° C., about −40° C., about−50° C., about −60° C., about −70° C., or about −80° C.), for example,at a temperature from about 0° C. to about 25° C.

In yet another aspect, the present invention is directed to method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate.The method includes keeping the polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with thevapor of a solvent. In one embodiment, the solvent can totally orpartially dissolve the polymorphic Form A of bazedoxifene acetate.Applicants have surprisingly found that Form A can partially transforminto Form B in the presence of the vapor of a solvent such as ethanol.

In yet another aspect, the present invention is directed to a method ofenhancing the stability of polymorphic Form A of bazedoxifene acetate.The method includes keeping the polymorphic Form A of bazedoxifeneacetate in dry form and preventing the dry form from contacting with thevapor of a solvent and keeping the polymorphic Form A of bazedoxifeneacetate at a temperature below 25° C. or lower (as low as about −196°C., e.g., about 20° C., about 15° C., about 10° C., about 5° C., about0° C., about −5° C., about −10° C., about −20° C., about −30° C., about−40° C., about −50° C., about −60° C., about −70° C., or about −80° C.),for example, at a temperature from about 0° C. to about 25° C.

In one aspect, the present invention is directed to polymorphic Form Aof bazedoxifene acetate prepared according to the methods describedherein. In certain embodiments, the polymorphic Form A of bazedoxifeneacetate prepared according to such methods is more than 99% w/w pure,for example, more than 99.5% w/w or more than 99.9% w/w pure. In certainother embodiments, the polymorphic Form A of bazedoxifene acetatecontains less than 1% w/w of Form B, for example, less than 0.5% w/w or0.1% w/w Form B. Throughout the application, the purity of Form A ofbazedoxifene acetate refers to polymorphic purity.

The invention is further illustrated by the following examples. Theexamples are provided for illustrative purposes only. They are not to beconstrued as limiting the scope or content of the invention in any way.

EXAMPLES Example 1 Infrared (IR) Analysis of Polymorphic Form A and FormB of Bazedoxifene Acetate

The solid state of both polymorphic Form A and Form B of BazedoxifeneAcetate has a characteristic Infrared (IR) spectrum. The transformationfrom Form A to Form B can be followed “on-line” by FT-IR/ATR and FBRMtechnology (Lasentec probe). The “IR on-line” experiments can be carriedout using the system React-IR 4000 in the configuration that uses theprobe with diamond sensor ATR (Dicomp). The “size-distribution on line”experiments are executed by using the system Lasentec FBRM equipped withD600R probe.

IR measures are carried out opportunely placing a few mg of the powderof the sample on the diamond sensor ATR of the probe. The inquiredspectral interval is 4000-650 cm-1 with 4 cm-1 resolution (128 scans forevery collected spectrum). Some experiments are executed creating anethanol vapor atmosphere around the ATR sensor avoiding the directcontact between the liquid solvent and the powder of bazedoxifeneacetate.

Some characteristic absorption peaks of the polymorphic Form A and FormB of bazedoxifene acetate are shown in Table 2. FIG. 1 shows an overlayof IR spectra of polymorphic Form A and Form B of bazedoxifene acetate.The bottom portion of FIG. 1 is the IR spectrum for Form A while the topportion of FIG. 1 is the IR spectrum for Form B.

TABLE 2 IR Wavelength number (cm⁻¹) Form A 841 1242 1356 1466 Form B 8491207 1368 1449

Example 2 Differential Scanning Calorimetry (DSC) Analysis ofPolymorphic Form A and Form B of Bazedoxifene Acetate

Differential scanning calorimetry (DSC) is conducted with aluminumhermetic pans, generally in the temperature interval of 150°-190° C. at5° C./min. Form A and Form B can be distinguished by their respectivemelting point. The DSC results are summarized in Table 3. FIG. 2 is aDSC thermogram for polymorphic Form A of bazedoxifene acetate. FIG. 3 isa DSC thermogram for polymorphic Form B of bazedoxifene acetate. FIG. 4shows an overlay of DSC thermograms for polymorphic Form A and Form B ofbazedoxifene acetate.

TABLE 3 Solid state Onset (° C.)* Peak (° C.)* Energy (J/g)* Form A176.0-177.0 178.0-179.0 Endo 95-100 Form B 180.5-181.5 182.0-182.8 Endo115-120 *Medium values from repeated analysis on samples considered purepolymorph and on HPLC specification.

The DSC technique can be used to quantitatively determine the presenceof polymorphic Form B of bazedoxifene acetate in batches produced aspolymorphic Form A of bazedoxifene acetate. FIG. 5 shows an example of aForm A batch with a content of Form B less than 0.1% w/w.

Example 3 Thermogravimetric Analysis (TGA) of Polymorphic Form A andForm B of Bazedoxifene Acetate

Thermogravimetric Analysis (TGA) is conducted with a platinum pan in thetemperature range of 25°-280° C. at 4° C./min. in modality “High-ResTGA”. During the heating (in an open system), polymorphic Form A andForm B of bazedoxifene acetate release acetic acid above 100° C., andgoes to completion generally between 235° and 245° C. The amount of theweight loss is between 11 and 12% and correspond to acetic acid ofneutralization (theoretical 10.8%). The TGA profile of the acetic acidloss of Form A and Form B is subdivided into three fractions. Thequantity of each fraction is characteristic of every single batch. FIG.6 shows a TGA curve for polymorphic Form A of bazedoxifene acetate. FIG.7 shows a TGA curve for polymorphic Form B of bazedoxifene acetate.

Example 4

Preparation of Bazedoxifene Acetate

A hydrogenation vessel is charged with hexamethyleniminobenzyloxy indole(64.4 Kg), ethyl acetate (95.7 Kg, 106.3 L), ethyl alcohol (244.6 Kg,309.7 L) and palladium/C5 (2.5% p/p, 2.54 Kg) under nitrogen. The vesselis degassed with hydrogen and then is recharged with hydrogen up to thepressure of 2 bar. The reaction mixture is heated to about 50±2° C., andthe hydrogen pressure is finally set at 4 bar. After about 2 hours fromthe end of the hydrogen absorption, the vessel is degassed up to 0.1 barand an HPLC analysis of the reaction mixture is performed to ensure thatthe reaction is complete. After a positive response of the analysis, themixture is cooled to about 20°-30° C., and the vessel is degassed withnitrogen. Then the vessel is charged with ascorbic acid (0.50 Kg) andthe internal temperature is set at about 40°-50° C. The solution isstirred at about 40°-50° C. for about 20 min.

The solution is then filtered under nitrogen through a plate filter (Theplate filter is prepared as follows: Celite (2.0 Kg) is suspended inethyl alcohol denatured with acetone/cyclohexane (a total of 60.0 Kg).The suspension is recycled with a centrifugal pump through the filterfor about 30 min. The filter is maintained full of solvent, then, about2 hours before filtering the solution, the jacket of the filter isfilled with water at about 60° C.), washed with ethanol denaturedcyclohexane/acetone (a total of 4.0 Kg, in two portions). Then undernitrogen glacial acetic acid (2.0 Kg) is added to the filtered solutionthrough a charging vessel and the solution is stirred for about 20 min.and then seeded with bazedoxifene acetate Form A (0.1 Kg). Thetemperature of the solution is kept at about 30° C. for about 30-40 min.and then glacial acetic acid (6.9 Kg) is charged in about two hours togive a suspension.

The suspension is cooled to about 0° C. in about 1 hour, left at about0° C. for about 2 hours, then centrifuged in two portions, and eachportion is washed twice with 7.3 Kg of ethyl alcohol denatured withcyclohexane/acetone. About 55 Kg of wet product are obtained. Afterdrying under vacuum at about 50° C., the yield was 46 Kg of bazedoxifeneacetate Form A. The yield for this step is about 86-88% and the purityof the final product is about 99% or higher.

Example 5 Preparation of Bazedoxifene Acetate—Catalyst Study

It is desirable to decrease the quantity of catalyst while achieving thesame or better performances, i.e. maintaining an acceptable productivityper hour, for the hydrogenation step. However, initial tests showed thatit was not possible to decrease the catalyst quantity without reducingsignificantly the reaction rate. See, for example, Example 1 in US2005/0227965, where the hydrogenation step therein took 20 hours.Applicants have surprisingly found that the catalyst quantity can besignificantly decreased with certain types of catalyst under suitableconditions. Table 4 lists the tests in which the catalyst quantity andits concentration are modified.

TABLE 4 Amount of Catalyst Solvent (ml/g mol/mol Lab hexamethylenimino-hexamethylenimino- Reaction Experiment^(a)) benzyloxy indole) Catalystbenzyloxy indole Time (hrs) 5.1 Ethyl acetate:Ethanol Pd(10%)—C dry0.047   1.5 2.25:5.25 5.2 Ethyl acetate:Ethanol Pd(10%)—C dry 0.02 72.35:3.30 5.3 Ethyl acetate:Ethanol Pd(5%)—C dry 0.02 <5^(b)) 2.00:3.105.4 Ethyl acetate:Ethanol Pd(5%)—C dry 0.01 2 1.45:2.35 5.5 Ethylacetate:Ethanol Pd(5%)—C dry 0.003 6 1.45:1.90 5.6 Ethyl acetate:Ethanol“Pearlman 0.003 1 1.45:1.90 like” catalyst Pd(5%)—C, 50% wet^(a))temperature 50° C. pressure 4 bar; ^(b))The first analyticalcontrol showed complete conversion

Experiment 5.6 in Table 4 shows that with a Pearlman type catalyst(non-reduced Pd), the hydrogenation time is cut down to 1 hour.Nevertheless, experiments with very low catalyst concentrations (1-3mmol/mol hexamethyleniminobenzyloxy indole) can cause the reaction to bevery sensitive to small quantities of poisonous substances contained inthe catalyst or formed during the debenzylation process. Thus, it may bedesirable to use a quantity of catalyst higher than the lowconcentrations of 1-3 mmol/mol, for example, in an amount of 6 mmol/molhexamethyleniminobenzyloxy indole for the hydrogenation process.

Additionally, two catalysts are compared with the catalyst amount usedbeing equal and all the other hydrogenation conditions being the same.One catalyst is Engelhard 5% Pd on Carbon Powder catalyst code 5016 andthe other is Engelhard 5% Pd on Carbon Powder DeLink code 5398. Aremarkable increase of speed (more than 300%) is observed for Engelhard5% Pd on Carbon Powder DeLink code 5398 at the same concentration.

Example 6 Preparation of Bazedoxifene Acetate—Solvent Study

Table 5 shows that the hydrogenation reaction is slow when each oftoluene and ethyl acetate is used at about 26° C. (see experiments 6.2and 6.3). The reaction time to complete the reaction is reduced whendenatured ethyl alcohol is used at about 28° C. (see experiment 6.1).The denatured ethyl alcohol used includes: (a) a 95:3:5 (v/v) mixture ofethyl alcohol, cyclohexane and methyl alcohol; and (b) a 95:3:5 (v/v)mixture of ethyl alcohol, cyclohexane and acetone. No differences inreaction time are observed using these two solvent mixtures. Thereaction time is reduced significantly when a mixture of AcOEt and EtOHis used at about 50° C. (see experiment 6.4).

TABLE 5 Lab Solvent quantity (ml)/g Temper- Reaction Experi-hexamethylenimino- ature time ment ^(a)) Solvent benzyloxy indole ° C.(hrs) 6.1 Denatured 8 28 15 Ethanol 6.2 ^(b)) Toluene 7.5 26 20 6.3^(c)) AcOEt 6.5 26 72 6.4 ^(d)) AcOEt-EtOH 2.25 + 5.25 50 1.5 ^(a))Catalyst Pd (10%)/C, 0.05-0.07 mol/mol hexamethyleniminobenzyloxyindole, 4 bar; ^(b)) 70% of unconverted raw material; ^(c)) 5% ofunconverted raw material; ^(d)) 0.047 mol of Pd/molhexamethyleniminobenzyloxy indole.

Example 7 Stability Study of Wet Polymorphic Form A of BazedoxifeneAcetate

Example 7 shows the effect of different solvents in the transformationof wet bazedoxifene acetate Form A to Form B. A portion of thecrystallization slurry of bazedoxifene acetate Form A is collected.After filtering on gooch, the wet bazedoxifene acetate Form A is dividedinto two portions that are washed with ethanol (experiment 7.1) and withethyl acetate (experiment 7.2) respectively. The GC data of the solventsin the two wet products show that the product from experiment 7.1 ismainly wet of ethanol, while the product from experiment 7.2 is almostexclusively wet of ethyl acetate, and their respective Loss on Drying(LOD) is of 14.5% and 16%. Tables 6 and 7 and FIGS. 8 and 9 list thecontent of Form B vs. time and vs. temperature for the two samples fromexperiments 7.1 (wet of EtOH) and 7.2 (wet of EtOAc).

TABLE 6 Stability of Bazedoxifene Acetate Form A Wet of EtOH % Form Bbatch 7.1 (LOD 14.5%) hrs 5° C. 10° C. 20° C. 0 0.0 0.0 0.0 6 0.0 0.10.4 20 2.5 4.4 30.0 44 14.5 68.0 100.0

TABLE 7 Stability of Bazedoxifene Acetate Form A Wet of EtOAc % Form Bbatch 7.2 (LOD 16%) hrs 5° C. 10° C. 20° C. 0 0.0 0.0 0.0 6 0.0 0.0 0.020 0.2 2.0 2.8 44 10.7 55.2 66.6

Comparing the two cases, the transformation rate of Form A into Form Bis higher for the batch washed with EtOH than that washed with EtOAc.This trend is particularly remarkable in the first 20 hours: in the sametemperature conditions batch 7.1 is characterized by at least a doublequantity of Form B with respect to batch 7.2. However, ethyl acetateseems only to slow down the transformation.

Example 8 Stability Study of Dry Polymorphic Form A of BazedoxifeneAcetate

Two dry samples of polymorphic form A of bazedoxifene acetate (batchesthat do not contain Form B), are kept at 50° C. in normal atmosphere for50 days and no variations in the polymorph content are detected. Anotherdry sample of polymorphic form A of bazedoxifene acetate (that containsabout 1% of Form B) is heated to 150° C. (near its melting point) and aDSC analysis of the sample does not reveal any variations in the contentof Form B.

Other treatments such as industrial granulation do not appear to causetransformation of the dry product from Form A into Form B. Tenindustrial batches are tested before and after granulation. Table 8shows that there are no differences in the content of Form B in the drysamples of bazedoxifene acetate Form A.

TABLE 8 Granulation Effect on the Polymorphic Transformation of Form Aof Bazedoxifene Acetate % Form B % Form B prior to after batchgranulation granulation 8.1 n.d n.d. 8.2 n.d. n.d. 8.3 n.d. n.d. 8.4 0.30.2 8.5 0.5 0.6 8.6 n.d. 0.1 8.7 0.3 0.2 8.8 n.d. n.d 8.9 n.d. n.d. 8.10n.d. n.d.

1. A method of enhancing the stability of polymorphic Form A ofbazedoxifene acetate, the method comprising (a) keeping said polymorphicForm A of bazedoxifene acetate in dry form and preventing the dry formfrom contacting with a solvent; or (b) keeping said polymorphic Form Aof bazedoxifene acetate in dry form and preventing the dry form fromcontacting with the vapor of a solvent.
 2. The method of claim 1,wherein said solvent can totally or partially dissolve said polymorphicForm A of bazedoxifene acetate.
 3. The method of claim 1, furthercomprising keeping said polymorphic Form A of bazedoxifene acetate at atemperature below 25° C. or lower.